In the DPP lifestyle cohort, meeting the 7% weight loss goal via a hypocaloric low-fat diet and 150 min per week of moderate-intensity physical activity was strongly correlated with the prevention of diabetes in both sexes. Although men in the ILS group lost significantly more weight and reported more physical activity than women, their rate of progression to diabetes (or regression to normal glucose tolerance) was the same. The present analyses suggest that the lack of greater benefit in the men may have been caused by a greater load of baseline risk factors. Of the cardiometabolic and diabetes risk factors assessed at baseline, women had higher risk in two (higher BMI and less physical activity), whereas men had higher risk in six (older age; higher fasting glucose level, waist circumference, and blood pressure; and lower HDL and insulin secretion). We explored the possibility that lack of greater benefit in the men could be due to a weaker effect of ILS on risk factors for diabetes in men versus women. To control for sex difference in levels of success with ILS, groups were stratified by weight loss as an objective measure of adherence (since diet and activity information was based on self-report) and also because weight loss is more closely related to diabetes prevention than the manner in which it occurs (8
). When stratified by weight loss, reduction in cardiometabolic and diabetes risk factors was actually greater in men than in women. Nevertheless, fasting glucose was only slightly modified by ILS and appeared to be more important in the development of diabetes in men than the development of diabetes in women. Greater success with ILS did not translate into reduced incidence of diabetes in men versus women, in part because of the higher baseline risk factors, especially fasting glucose concentration, in men in the DPP.
With more numerous risk factors at baseline, men conceivably had a greater risk for diabetes than women from the outset of the DPP. Cox proportional hazards modeling adjusted for age and ethnicity demonstrated a nonsignificant trend toward a 20% higher risk of diabetes in male than in female placebo participants in the DPP (P
= 0.08). Several large trials, including the Strong Heart Study (9
) and the Women's Health Study (10
), contend that the type and/or potency of cardiometabolic and diabetes risk factors may be different in men and women. In particular, older age, higher blood pressure, and the presence of metabolic syndrome have been shown to convey greater cardiometabolic and/or diabetes risk in women (11
). Certainly, diabetes itself has long been appreciated as a stronger relative risk factor for cardiovascular disease in women (13
). Therefore, the fact that older age, higher plasma fasting glucose, and features of metabolic syndrome were more common in men than women at baseline in the DPP makes it worth considering whether the more numerous baseline risk factors in men actually conferred greater diabetes risk or simply equalized the risk between the sexes. A meta-analysis of 16 trials comparing the impact of sex with that of risk factors for cardiovascular disease revealed that cardiometabolic risk could be predicted by cardiometabolic risk factors but not by sex per se (14
). In sum, men in the DPP had more numerous risk factors than women, presumably making their baseline risk for diabetes higher. Whether these risk factors modified disease risk differently in men versus women in the DPP remains speculative.
Higher fasting glucose concentration in men versus women in the DPP is consistent with repeated observations in population studies (15
). Although both fasting and 2-h glucose concentrations are positively associated with diabetes risk, diabetes incidence rises exponentially as fasting glucose levels increase but only linearly when 2-h glucose levels increase (17
). Therefore, when participants were enrolled in the DPP (requiring elevation of both fasting and 2-h glucose values), the men started with higher diabetes risk due to higher initial fasting glucose values. Strong evidence exists that those with high fasting and 2-h glucose values progress to diabetes more rapidly than those with only one or the other (18
). Although no overall sex difference was observed in incident diabetes in the DPP, sex difference in manner of diagnosis was observed. More women than men progressed to diabetes based on 2-h glucose criteria, whereas more men than women progressed based on the combination of fasting and 2-h glucose criteria. Together, these observations highlight the importance of fasting hyperglycemia as a risk factor and route of progression to diabetes in men.
Strengthening its role as a pivotal risk factor, fasting glucose was only modestly affected by lifestyle intervention. ILS improved many risk factors for diabetes among participants of the DPP but appeared to be more robust in lowering 2-h than fasting glucose levels. In those randomized to ILS, 2-h glucose concentration during the OGTT fell 5–26%, whereas fasting glucose concentration fell only 1–8%. Two-hour glucose concentration decreased steadily in response to increased success with ILS in both men and women; however, among those who lost >3% body weight, the decrease was greater in men. Although no weight change was noted among placebo participants in the DPP, a decrease in 2-h glucose at year 1 was seen in men but not women. This may relate to the fact that men were more physically active than women upon entry and throughout the DPP. Consistent with the recently published AusDiab study (20
), 2-h glucose appears to be more strongly modified by physical activity than fasting glucose, and the effect may be independent of weight loss.
The greater decline in 2-h glucose in men versus women who lost >3% body weight in the DPP might be explained by sex differences in glucose uptake and oxidation during physical activity (21
). Clinical studies suggest that men rely proportionately more on carbohydrate and women proportionately more on lipid during submaximal physical activity (21
). This is evidenced by a higher respiratory exchange ratio in men (21
) during exercise at a similar intensity. The preferential use of carbohydrate as a fuel during physical activity in men would mandate postexercise repletion of glucose stores and might explain the greater lowering of 2-h glucose among men with >3% weight loss in the DPP. In addition to 2-h glucose concentration, numerous diabetes and cardiometabolic risk factors were favorably modified by weight loss from ILS. Among those who lost >3% body weight, men appeared to have greater risk factor reduction with respect to insulin concentration and insulin resistance (at 3–7% weight loss), as well as triglyceride concentration and A1C (at >7% weight loss). Although the trends were not consistent between strata of weight loss (as with 2-h glucose), they cumulatively represent improved insulin action, which also likely relates to greater active lean mass in men compared with women.
Several limitations of the current study are worth noting. First, although randomized, the study was not balanced with respect to sex or powered to examine sex differences a priori. Post hoc analyses may yield erroneous results, especially when making multiple comparisons. Second, data on physical activity and dietary intake were self-reported and lack the robustness of a supervised intervention. Finally, the physiological or behavioral basis for the greater success in meeting ILS goals among men versus women is unknown.
In summary, meeting the 7% weight loss goal through ILS strongly correlated with the prevention of diabetes in the DPP participants. Surprisingly, in the ILS group, men lost significantly more weight and were more active than women and yet incident diabetes (or return to normal glucose tolerance) did not differ significantly by sex. The present analyses suggest that the lack of greater benefit in the men may have been obscured by their more numerous and/or more severe baseline risk factors, especially fasting glucose concentration, which was modified only modestly by ILS. Fasting and 2-h glucose concentration may impart different risk for diabetes in men and in women, in that progression to diabetes appeared more dependent on fasting glucose in men and more dependent on 2-h glucose in women. Prospective studies powered to examine sex-specific consequences of different prevention strategies would be useful.